Coated tablet formulations and uses thereof

ABSTRACT

The present invention provides coated tablet formulations comprising neratinib maleate, and improved methods for making such coated tablets.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 61/259,403,filed Nov. 9, 2009, which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to oral pharmaceutical formulations ofneratinib provided in the form of coated tablets prepared by fluid bedgranulation or by wet granulation, and improved methods of making thesecoated tablets.

BACKGROUND OF THE INVENTION

Protein kinases are important in the transmission of biochemicalsignals, which initiate cell replication. Protein kinases are enzymesthat catalyze the transfer of a phosphate group from ATP to an aminoacid residue, such as tyrosine, serine, threonine, or histidine on aprotein. Regulation of these protein kinases is essential for thecontrol of a wide variety of cellular events including proliferation andmigration. Specific protein kinases have been implicated in adverseconditions including cancer [Traxler, P. M., Exp. Opin. Ther. Patents,8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)],restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw,Trends Pharmacol. Sci. 16, 401 (1995)], atherosclerosis [Raines, E. W.,Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug DiscoveryToday, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] andosteoporosis [Boyce, J. Clin. Invest., 90, 1622 (1992)]. Compoundscapable of inhibiting the activity of receptor tyrosine kinases areknown to be useful in the treatment of cancers, including but notlimited to for example, non-small cell lung cancer (NSCLC), breastcancer, polycystic kidney disease, colonic polyps, and stroke inmammals. A specific kinase inhibitor is(E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide,also known as neratinib. Nerartinib is a weak base having lowbioavailability and low solubility in both water and alcohol.

Neratinib maleate particles exhibit very high surface free energy, (workof cohesion=45.62 mN/m). This property renders the primary particlesvery cohesive and prone to aggregation as described by B. Janczuk and T.Bialopiotrowicz, “Surface Free-Energy Components of Liquids and LowEnergy Solids and Contact Angles,” in J. Colloid Interf. Sci. 127(1989), p. 189-204; W. R. Good, “A Comparison of Contact AngleInterpretations,” in J. Colloid Interf. Sci. 44 (1973), p. 63; M. D.Lechner (Ed.), Landolt Börnstein, New Series, Vol. IV/16, “SurfaceTension of Pure Liquids and Binary Liquid Mixture,” Springer Verlag,1998; and J. J. Jasper, “The Surface Tension of Pure Liquid Compounds,”in J. Phys. Chem. Ref. Data, Vol. 1, No. 4, 1972, p. 859. As aconsequence of cohesiveness, neratinib maleate powder does not lenditself easily to pharmaceutical operations such as mixing, flow orfluidization especially when it constitutes a high proportion in acomposition. Due to these limitations, it was not possible to develop aneratinib maleate formulation comprising a capsule or tablet of higherstrength employing a direct compression or roller compaction processessuccessfully. A formulation using a conventional wet granulation methodled to chemical degradation and stability issues.

SUMMARY OF THE INVENTION

It is desirable to provide a neratinib maleate formulation, where thesurface property of the active ingredient is modified by spraying orotherwise applying a substance, such as a polymer like povidone, of lowsurface energy (for instance about 38 mN/m) on the surface of neratinibmaleate particles.

The present invention provides pharmaceutically acceptable solidcompositions suitable for oral administration comprising the activeingredient neratinib maleate. In certain embodiments, such solidcompositions are provided in the form of coated tablets prepared byfluid bed granulation. In some embodiments, the present inventionprovides a unit dosage form comprising neratinib maleate.

The present invention provides a pharmaceutically acceptable compositioncomprising: a granulation comprising intragranular components: (a) 10-70weight percent neratinib maleate; (b) 15-65 weight percent of one ormore fillers; (c) 0-8 or 0.5-8 weight percent of one or moredisintegrants; and (d) 0.2-8 weight percent, in certain embodiments0.2-6 weight percent, of one or more glidants; and (e) 5-15 weightpercent of one or more surface modifying agents. The granulation iscombined with extragranular components (f) 1-25 or 4-25 weight percentof one or more fillers; (g) 1-8 or 0-8 weight percent of one or moredisintegrants and (h) 0.1-3 or 0.5-3 weight percent of one or morelubricants, and then compressed into tablets or dry-filled intocapsules.

The present invention provides a pharmaceutically acceptable compositioncomprising: a granulation comprising intragranular components (a) 10-70weight percent of neratinib maleate; (b) 15-65 weight percent ofmannitol and microcrystalline cellulose; (c) 0.5-8 weight percent ofcrospovidone or croscarmellose sodium; and (d) 0.2-8 weight percent, incertain embodiments 0.2-6 weight percent, of colloidal silicon dioxide,and (e) 5-15 weight percent of povidone. The granulation is combinedwith extragranular components (f) 1-25 or 4-25 weight percent ofmicrocrystalline cellulose; (g) 0-8 or 1-80-8 weight percent ofcrospovidone or croscarmellose sodium and (h) 0.1-3 or 0.5-3 weightpercent of magnesium stearate, and then compressed into tablets ordry-filled into capsules.

The present invention also provides methods of preparing stable,pharmaceutically acceptable neratinib-maleate formulations for oraladministration comprising components described above and herein, whichallow for improved processing characteristics while maintainingacceptable pharmokinetic properties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 summarizes mean pharmacokinetic parameters versus time forneratinib maleate following the administration of immediate releasetablet formulations of neratinib with different dissolution rates. TRrefers to a rapid dissolving tablet, while SR dissolve relativelyslowly. The presented data shows plasma concentration levels followingadministration of a single oral dose (240-mg tablet) in subjects.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

1. Definitions

As used herein, an “effective amount” of a compound or pharmaceuticallyacceptable composition can achieve a desired therapeutic and/orprophylactic effect. In some embodiments, an “effective amount” is atleast a minimal amount of a compound, or composition containing acompound, which is sufficient for treating one or more symptoms of adisorder or condition associated with modulation of protein tyrosinekinases. In certain embodiments, an “effective amount” of a compound, orcomposition containing a compound, is sufficient for treating symptomsassociated with, a disease associated with an aberrant tyrosine kinasereceptor (e.g. cancer, including malignant and benign tumor growths).

The term “subject”, as used herein, means a mammal and includes humanand animal subjects, such as domestic animals (e.g., horses, dogs, cats,etc.).

The terms “suffer” or “suffering” as used herein refers to one or moreconditions that a patient has been diagnosed with, or is suspected tohave.

The terms “treat” or “treating,” as used herein, refers to partially orcompletely alleviating, inhibiting, delaying onset of, preventing,ameliorating and/or relieving a disorder or condition, or one or moresymptoms of the disorder or condition.

“Therapeutically active agent” or “active agent” refers to a substance,including a biologically active substance, that is useful for therapy(e.g., human therapy, veterinary therapy), including prophylactic andtherapeutic treatment. Therapeutically active agents include organicmolecules that are drug compounds, peptides, proteins, carbohydrates,monosaccharides, oligosaccharides, polysaccharides, nucleoprotein,mucoprotein, lipoprotein, synthetic polypeptide or protein, smallmolecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA,RNA, nucleotide, nucleoside, oligonucleotides, antisenseoligonucleotides, lipid, hormone, and vitamin. Therapeutically activeagents include any substance used as a medicine for treatment,prevention, delay, reduction or amelioration of a disease, condition, ordisorder. Among therapeutically active agents useful in the formulationsof the present invention are opioid receptor antagonist compounds,opioid analgesic compounds, and the like. Further detailed descriptionof compounds useful as therapeutically active agents is provided below.A therapeutically active agent includes a compound that increases theeffect or effectiveness of a second compound, for example, by enhancingpotency or reducing adverse effects of a second compound.

“Unit dosage form” as used herein refers to a physically discrete unitof inventive formulation appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of thecompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; activity of specific active agent employed;specific composition employed; age, body weight, general health, sex anddiet of the subject; time of administration, and rate of excretion ofthe specific active agent employed; duration of the treatment; drugsand/or additional therapies used in combination or coincidental withspecific compound(s) employed, and like factors well known in themedical arts.

In dry granulation (slugging or roller compaction) intragranularmaterials are blended to prepare slugs or roller compaction. Material ismilled and blended with extragranular materials followed by capsulefilling or tablet 20 compression. Wet granulation entails blendingintragranular materials. Wet granulate the blend with water, with orwithout a binder, (using high sheer, low sheer granulators) and dry(using temperatures up to 100° C.). Material is milled and blended withextragranular materials followed by capsule filling or tabletcompression. See, 25 Handbook of Pharmaceutical Granulation Technology,1997, Dilip Parikh, Marcel Dekker, Inc. ISBN 0-8247-9882-1, pages338-368.

2. Pharmaceutically Acceptable Compositions and Formulations

In certain embodiments, the present invention provides apharmaceutically acceptable composition for intravenous administrationcomprising: neratinib maleate. Neratinib and other4-amino-3-cyanoquinoline compounds are disclosed in U.S. Pat. Nos.6,002,008, 6,288,082, 6,297,258, 6,384,051 and 7,399,865. Neratinib hasthe following chemical structure:

and is isolated as a free base or prepared as a pharmaceuticallyacceptable salt, such as a maleate salt. Neratinib is a weak base withan intrinsic low solubility in water.

In certain embodiments, solid pharmaceutically acceptable compositionsof neratinib maleate are provided in the form of tablets prepared byfluid bed granulation. Intragranular particulate components comprisingan active ingredient, namely neratinib maleate, one or more fillers, adisintegrant and a glidant are sprayed with, or otherwise wholly orpartially covered with, a surface modifying agent, such as povidone, tolower the surface energy of the particles. The fluid bed process isemployed to effectively modify the surface behavior of the particulateactive ingredient, so that any water instantly dries and does not bringabout any polymorphic or chemical change in active during the process.The surface property of the active ingredient is modified by spraying apolymer, for instance povidione, having a low surface energy (forinstance of about 38 mN/m) on the surface of the intragranularparticles. After the modification of surface properties, theintragranular particles are no longer cohesive, or are significantlyless cohesive, and are easily rendered to all pharmaceutical operations.The surface-modified intragranular particles are then further processed,typically by combining with extragranular components typicallycomprising a filler, a disintegrant and a lubricant, and furtherprocessed into dry-filled capsules or tablets for oral administration.The surface modified intragranular components can also be used directlyto make dosage forms without combination with extragranular components,for instance in connection with dry-filled capsules.

In certain embodiments, solid pharmaceutically acceptable compositionsof neratinib maleate are provided in the form of tablets prepared by wetgranulation. Increasing the glidant and lubrication levels provided animproved neratinib maleate formulation that flowed without aggregationof granules, as compared to a wet granulated neratinib maleateformulation used in clinical trials. The glidant was increased from 0.5%to 2.0% to improve the flow of the pre-blended material. The picking andsticking issues observed during compression were eliminated byincreasing the lubrication level from 0.5% to 3.0%, in certainembodiments 0.5% to 2.0%. In certain embodiments the amount of lubricantsuch as magnesium stearate needed is as low as 0.2% or even 0.1%. Theincrease in amount of glidant and lubricant was compensated by acorresponding reduction in the amount of fillers added to theformulation.

In some embodiments, the active ingredient comprises a4-amino-3-cyanoquinoline compound such as neratinib, specificallyneratinib maleate, or a pharmaceutically acceptable salt thereof.Suitable examples of 4-amino-3-cyanoquinoline compounds are disclosed inU.S. Pat. Nos. 6,002,008, 6,288,082, 6,297,258, 6,384,051 and 7,399,865.According to one embodiment, neratinib maleate is the active ingredient.The active ingredient comprises from about 10 weight % to about 70weight %, including from 20-50 weight % and about 35 weight % or 41weight %, based upon total weight of the formulation.

According to one embodiment, a surface modifying agent is sprayed ontoparticulate intragranular components before further processing withextragranular components. Suitable surface modifying agents include, butare not limited to for example, povidone, gelatin, starch, hydroxypropyl methyl cellulose and hydroxy propyl cellulose. In one embodiment,povidone is the surface modifying agent. The surface modifying agentcomprises from about 1 weight % to about 15 weight %, including from3-12 weight % and from 5-10 weight %, based upon total weight of theformulation.

Suitable fillers (also referred to as “diluents”) are known in the art.For example, suitable fillers include but are not limited to starch,dextrin, sucrose, Sorbitol, Sodium Saccharin, Acesulfame potassium,Xylitol, Aspartame, Mannitol, starch, PVP (polyvinyl pyrrolidone), lowmolecular weight HPC (hydroxypropyl cellulose), microcrystallinecellulose (MCC), low molecular weight HPMC (hydroxypropylmethylcellulose), low molecular weight carboxymethyl cellulose,ethylcellulose, dicalcium phosphate, silicified microcrystallinecellulose, alginates, gelatin, polyethylene oxide, acacia, dextrin,sucrose, magnesium aluminum silicate, and polymethacrylates. Fillersinclude agents selected from the group consisting of microcrystallinecellulose, starch, lactitol, lactose, a suitable inorganic calcium salt,sucrose, glucose, mannitol, silicic acid, or a combination thereof. Thefillers, as an intragranular component, comprise from about 15 weight %to about 65 weight %, based upon total weight of the formulation. In oneembodiment, the intragranular filler is a combination of mannitol andmicrocrystalline cellulose. The fillers, as an extragranular component,comprise from about 4 weight % to about 25 weight %, based upon totalweight of the formulation. In one embodiment, the extragranular filleris microcrystalline cellulose.

Suitable disintegrants are known in the art and include but are notlimited to, agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, sodium carbonate, crospovidone (cross-linkedPVP), sodium carboxymethyl starch (sodium starch glycolate),cross-linked sodium carboxymethyl cellulose (croscarmellose),pregelatinized starch (starch 1500), microcrystalline starch, waterinsoluble starch, sodium starch glycolate, potassium polacrilin, sodiumalginate, calcium carboxymethyl cellulose, magnesium aluminum silicate(Veegum) or a combination thereof. In some embodiments, a disintegrantis crospovidone. The disintegrant, as an intragranular component,comprises from about 0 or 0.5 weight % to about 8 weight %, includingfrom 0 or 0.5-6 weight % and from 0 or 0.5-50-5 weight %, based upontotal weight of the formulation. The disintegrant, as an extragranularcomponent, comprises from about 0 or 1 weight % to about 8 weight %,based upon total weight of the formulation.

A glidant is used as an intragranular component of the formulation.Suitable glidants include, without limitation, colloidal silicondioxide, talc, magnesium carbonate, calcium silicate, fumed silicondioxide, and combinations thereof. In some embodiments, the glidant iscolloidal silicon dioxide. The amount of glidants used is 0.2-8 weightpercent, or 0.2-5 weight percent, including 0.5-2 weight %, based on thetotal weight of the formulation.

A lubricant is used as an extragranular component of the formulation.Suitable lubricants or glidants include for example stearates, sodiumstearyl fumarate, magnesium salts and magnesium stearate. In someembodiments, the lubricant is magnesium stearate. The amount oflubricants used is 0.2-4 weight percent, in certain embodiments 0.5-3weight %, based on the total weight of the formulation.

Provided compositions may be formulated into a unit dosage form. Suchformulations are well known to one of ordinary skill in the art. Incertain embodiments, the present invention provides a formulationcomprising a solid dosage form as a tablet. In other embodiments, thepresent invention provides a solution for oral administration. In someembodiments, a unit dosage form contains 5, 10, 20, 25, 40, 50 mg, 75mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg,525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg,750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg,975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg,1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg,1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg of neratinib Insome embodiments, a unit dosage form contains between 5 mg and 500 mg,inclusive, or between 10 mg and 450 mg, inclusive, of neratinib. In someembodiments, a unit dosage form contains 40 mg, 80 mg, 100 mg, 120 mg,240 mg, 360 mg, or 480 mg. In some embodiments, a unit dosage formcontains more than 500 mg of neratinib.

In some embodiments, satisfactory results are obtained when thecompounds of the invention are administered at a daily dosage of fromabout 0.5 to about 1000 mg/kg of body weight, optionally given individed doses two to four times a day, or in sustained release form. Thetotal daily dosage is projected to be from about 1 to 1000 mg,preferably from about 2 to 500 mg. Dosage forms suitable for internaluse comprise from about 0.5 to 1000 mg of the active compound inintimate admixture with a solid or liquid pharmaceutically acceptablecarrier. This dosage regimen may be adjusted to provide the optimaltherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation.

For the treatment of cancer, the inventive formulations of thisinvention can be administered in combination with other anti-tumorsubstances or with radiation therapy. These other substances orradiation treatments can be given at the same or at different times asthe compounds of this invention. These combined therapies may effectsynergy and result in improved efficacy. For example, the compounds ofthis invention can be used in combination with mitotic inhibitors suchas taxol or vinblastine, alkylating agents such as cisplatin orcyclophosamide, anti-metabolites such as 5-fluorouracil or hydroxyurea,DNA intercalators such as adriamycin or bleomycin, topoisomeraseinhibitors such as etoposide or camptothecin, antiangiogenic agents suchas angiostatin, and antiestrogens such as tamoxifen.

Based on the results disclosed for neratinib and other4-amino-3-cyanoquinoline compounds in U.S. Pat. No. 6,297,258, theinvented formulations are useful antineoplastic agents of significantefficacy, which are useful in treating, inhibiting the growth of, oreradicating neoplasms. In particular, the compounds of this inventionare useful in treating, inhibiting the growth of, or eradicatingneoplasms that express the receptor protein produced by the erbB2 (Her2)oncogene.

3. Combination Products and Combined Administration

In certain embodiments, inventive compositions, and formulationsthereof, may be administered alone to treat one or more disorders asdescribed herein, or alternatively may be administered in combinationwith (whether simultaneously or sequentially) one or more other activeagents useful to treat one or more disorders as described herein. Thus,an inventive composition, or formulation thereof, can be administeredconcurrently with, prior to, or subsequent to, one or more activeagents.

In certain embodiments, inventive compositions include one or more otheractive agents in addition to neratinib that is not neratinib. In someembodiments, inventive formulations comprise both another anticancercompound and neratinib.

The amount of additional active agent(s) present in combinationcompositions of this invention will typically be no more than the amountthat would normally be administered in a composition comprising thatactive agent as the only therapeutic agent. In certain embodiments ofthe present invention, the amount of additional active agent will rangefrom about 50% to 100% of the amount normally present in a compositioncomprising that compound as the only therapeutic agent.

4. Uses and Kits of Inventive Compositions

Provided compositions, and formulations thereof, are also useful intreatment of conditions including cancers.

In still further embodiments, veterinary applications (e.g., treatmentof domestic animals, e.g. horse, dogs, cats, etc.) of use of inventivecompositions, and formulations thereof, are provided. Thus, use ofprovided formulations in veterinary applications analogous to thosediscussed above for human subjects is contemplated.

It will also be appreciated that inventive compositions, andformulations thereof, can be employed in combination therapies, that is,an inventive composition, or formulation thereof, can be administeredconcurrently with, prior to, or subsequent to, one or more other desiredtherapeutics or medical procedures. Particular combination therapies(therapeutics or procedures) to employ in a combination regimen willtake into account compatibility of the desired therapeutics and/orprocedures and the desired therapeutic effect to be achieved. It willalso be appreciated that therapies employed may achieve a desired effectfor the same disorder (for example, a formulation may be administeredconcurrently with another compound used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic compounds which arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In other embodiments, inventive compositions, and formulations thereof,and unit dose forms are useful in preparation of medicaments, including,but not limited to medicaments useful in the treatment of cancer.

Still further encompassed by the invention are pharmaceutical packsand/or kits comprising inventive compositions, and formulations thereof,and a container (e.g., a foil or plastic package, or other suitablecontainer). Optionally instructions for use are additionally provided insuch kits.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

All features of each of the aspects of the invention apply to all otheraspects mutatis mutandis.

EXAMPLES Example 1 Preparation of Coated Tablets of a Neratinib MaleateFormulation by Fluid Bed Wet Granulation Process

A pharmaceutically acceptable formulation of neratinib mealate isprepared: a granulation comprising intragranular components (a) 10-70weight percent of neratinib maleate; (b) 15-65 weight percent ofmannitol and microcrystalline cellulose; (c) 0.5-8 weight percent ofcrospovidone or crosscarmellose sodium; (d) 0.2-8 weight percent ofcolloidal silicon dioxide, and (e) 5-15 weight percent of povidone. Thegranulation is combined with extragranular components (f) 4-25 weightpercent of microcrystalline cellulose; (g) 1-8 weight percent ofcrospovidone and (h) 0.5-3 weight percent of magnesium stearate, andthen compressed into tablets or dry-filled into capsules. This andcertain preferred ranges of materials are shown below in Table 1.

TABLE 1 Weight % Weight % Component Weight % range range Intra-granularcomponents HKI-272 Maleate, anhydrous 41 20-50 10-70 Mannitol 15-65Microcrystalline cellulose,  5-35 Crospovidone/croscarmellose 0.5-5.002-6 0.5-8  sodium Povidone 5-10  3-12  1-15 Colloidal Silicon Dioxide0.5-2.0  0.2-3  0.2-5  Extra-granular components Microcrystallinecellulose 4-25  4-25  4-25 Crospovidone/carmellose 1-8  1-8 1-8 sodiumMagnesium stearate 0.5-3.0  0.2-3.5 0.2-4.0 Total (Core Tablet) 1.1.11.1.2 1.1.3 Film coat: Opadry ®The formulation was prepared according to the following procedure:

-   -   1. Mixed neratinib maleate, mannitol, microcrystalline cellulose        and crospovidone and silicon dioxide. Any diffusive or        convective mixer may be used.    -   2. Dissolved povidone in purified water.    -   3. Fluidized the powder blend in step 1 and sprayed it with        solution prepared in step 2 in a suitable fluid bed granulator        and dryer.    -   4. Dried the granulation.    -   5. Milled the granulation.    -   6. Added microcrystalline cellulose and crospovidone to the        granulation in step 5 and mixed.    -   7. Added magnesium stearate to the mixture in step 6 and mixed.    -   8. Compressed the blend in step 7 into tablets of desired        strength.    -   9. Applied film-coat to compressed tablets using Opadry II of        desired color.    -   10. Alternatively the powder blend can be filled in capsules        shells.

Example 2 Unit Dosage Forms of an Exemplary Neratinib MaleateFormulation

Using the fluid bed process described in Example 1, different unitdosages of neratinib maleate were prepared from an exemplaryformulation, as summarized in Table 2.

TABLE 2 Granulation 40 mg 80 mg 240 mg Ingredient Function wt/wt (%)mg/tablet Mg/tablet mg/tablet Intragranular Components HKI-272Maleate^(a) Active 35.00 40.00 80.00 240.00 Mannitol (Pearlitol Diluent38.94 44.50 89.01 267.02 200 SD) Microcrystalline Diluent 10.56 12.0724.14 72.41 (Avicel PH 101) Crospovidone Disintegrant 3.00 3.43 6.8620.57 Povidone USP/K-25 Surface 5.00 5.71 11.43 34.29 Modifying AgentColloidal SiO2 Glidant 2.00 2.29 4.57 13.71 Extragranular ComponentsAvicel PH 101 Diluent 1.50 1.71 3.43 10.29 Crospovidone Disintegrant2.00 2.29 4.57 13.71 Mg Stearate Lubricant 2.00 2.29 4.57 13.71 TotalWt. 100.00 114.29 228.57 685.71 Film Coating: Opadry II Film Coat —3.429 — — (85F15443) Red (3%) Opadry II Film Coat — — 6.86 — (85F92177)Yellow (3%) Opadry II Film Coat — — — 20.57 (85F94211) Pink (3%) TotalTablet Wt — 117.714 235.43 706.28 ^(a)Weight percent as HKI-272 freebase.

Example 3 Coated Tablets of Targeted Release Neratinib MaleateManufactured by Spraying Povidone on Intragranular Components in a FluidBed

An exemplary targeted release (TR) neratinib maleate formulation issummarized in Table 3.

TABLE 3 40 mg 240 mg Tablet Tablet Ingredient % wt/wt (mg) (mg) FunctionIntragranular Components HKI-272 Maleate, anhydrous 35.00 40.0 240.00Active Mannitol 38.25 43.79 262.72 Filler Microcrystalline cellulose,12.75 14.50 86.99 Filler Crospovidone 3.00 3.43 20.57 DisintegrantPovidone 5.00 5.71 34.29 Surface Modifying Agent Colloidal SiliconDioxide 0.50 0.57 3.43 Glidant Extra-granular ComponentsMicrocrystalline cellulose 3.00 3.43 20.57 Filler Crospovidone 2.00 2.2913.71 Disintegrant Magnesium stearate 0.50 0.57 3.43 Lubricant Total(Core Tablet) 100.00 114.29 685.71 Film coat: Opadry ® 3.43 20.57 Filmcoat

Example 4 Coated Tablets of Slow Release Neratinib Maleate Manufacturedby Spraying Povidone on Intragranular Components in a Fluid Bed

An exemplary slow release (SR) neratinib maleate formulation issummarized in Tables 4A and 4B.

TABLE 4A mg/tablet Ingredient Name Function % Wt/Wt 240 mg TabletIntra-granular Components HKI-272 maleate Active 35.00 240.00 MannitolUSP Filler 41.81 286.69 Microcrystalline Cellulose NF Filler 9.19 63.02Crospovidone NF Disintegrant 0 Colloidal Silicon Dioxide, NF Glidant0.50 3.43 Povidone USP/K-25 Binder 10.00 68.57 Purified Water, EP/BP/USPSolvent — Extra-granular Components Microcrystalline Cellulose NF Filler— Crospovidone NF Disintegrant 0.50 3.43 Magnesium Stearate, NF/Ph/Lubricant 3.00 20.57 EU. (Vegetable grade),

TABLE 4B Granulation 40 mg 80 mg 240 mg Ingredient Function wt/wt (%)mg/tablet Mg/tablet mg/tablet Intragranular Components HKI-272 MaleateActive 35.00 40.00 80.00 240.00 Mannitol (Pearlitol Diluent 38.94 44.5089.01 267.02 200 SD) Microcrystalline Diluent 10.56 12.07 24.14 72.41(Avicel PH 101) Croscarmellose sodium Disintegrant 3.00 3.43 6.86 20.57Povidone USP/K-25 Surface 5.00 5.71 11.43 34.29 Modifying AgentColloidal SiO2 Glidant 2.00 2.29 4.57 13.71 Extragranular ComponentsAvicel PH 101 Diluent 1.50 1.71 3.43 10.29 Croscarmellose sodiumDisintegrant 2.00 2.29 4.57 13.71 Mg Stearate Lubricant 2.00 2.29 4.5713.71 Total Wt. 100.00 114.29 228.57 685.71 Film Coating: Opadry II FilmCoat — 3.429 — — (85F15443) Red (3%) Opadry II Film Coat — — 6.86 —(85F92177) Yellow (3%) Opadry II Film Coat — — — 20.57 (85F94211) Pink(3%) Total Tablet Wt — 117.714 235.43 706.28

Example 5 Drug Release Data

Drug release data are summarized for neratinib maleate formulations inExamples 3 and 4, as summarized in Table 5. Dissolution of tablets wascarried out employing 900 ml of 0.1N HCl as dissolution medium in USPdissolution apparatus 2, and a paddle speed of 50±1 rpm at 37±0.5° C.Samples were taken at specific time points and were analyzed by UVspectrometer at 266 nm.

TABLE 5 Dissolution data for Neratinib Maleate Formulations % DissolvedTime (minutes) TR Tablet Formulation SR Tablet Formulation 15 47 24 3083 43 45 99 64 60 99 82

Mean pharmacokinetic parameters for neratinib maleate in targetedrelease and slow release formulations following administration of asingle oral dose (240-mg tablet) in subjects were evaluated andsummarized in Table 6. The mean concentration versus time profiles fortargeted release and slow release formulations are summarized in FIG. 1.

TABLE 6 Summary of Mean Pharmacokinetic Parameters for Neratinib MaleateFormulations Following Single Oral Dose (240-mg tablet) in HealthySubjects Under Fed Conditions Mean ± SD (CV %) 240 mg TR 240 mg SR[Geometric Mean] (n = 26) (n = 26) C_(max) (ng/mL) 81.38 ± 27.49 (34) 82.21 ± 29.73 (36) [77.13] [77.12] t_(max) (hr) 5.00 6.00 (3.00, 12.00)(3.00, 12.00) AUC 1432 ± 450 (31)  1474 ± 467 (32) [1358]  [1393] 

What is claimed is:
 1. A pharmaceutically acceptable compositioncomprising: a granulation comprising intragranular components: (a) 10-70weight percent neratinib maleate; (b) 15-65 weight percent of one ormore fillers; (c) 0-8 weight percent of one or more disintegrants; (d)0.2-8 weight percent of one or more glidants; and (e) 5-15 weightpercent of one or more surface modifying agents; wherein the granulationis combined with extragranular components: (f) 1-25 weight percent ofone or more fillers; (g) 0-8 weight percent of one or moredisintegrants; and (h) 0.1-3 weight percent of one or more lubricants.2. A pharmaceutically acceptable composition comprising intragranularcomponents: 10-70 weight percent of neratinib maleate and 5-15 weightpercent of povidone; and extragranular components: microcrystallinecellulose, crospovidone and magnesium stearate.
 3. A pharmaceuticallyacceptable composition comprising intragranular components: (a) 10-70weight percent of neratinib maleate; (b) 15-65 weight percent ofmannitol, microcrystalline cellulose or a combination of both; (c) 0.5-8weight percent crospovidone, croscarmellose sodium or a combination ofboth; (d) 0.2-8 weight percent colloidal silicon dioxide; and (e) 5-15weight percent povidone; and extragranular components: (f) 1-25 weightpercent of microcrystalline cellulose; (g) 1-8 weight percent ofcrospovidone; and (h) 0.5-3 weight percent of magnesium stearate.
 4. Atablet comprising the composition of claim
 3. 5. A dry-filled capsulecomprising the composition of claim
 3. 6. The composition according toclaim 3, wherein the amount of neratinib maleate is about 41 weightpercent.
 7. The composition according to claim 3, wherein the amount ofmannitol and microcrystalline cellulose, as an intragranular component,is about 50 weight percent.
 8. The composition according to claim 3,wherein the amount of crospovidone, as an intragranular component, isabout 3 weight percent.
 9. The composition according to claim 3, whereinthe amount of povidone, as an intragranular component, is about 5 weightpercent.
 10. The composition according to claim 3, in the form of anoral dosage of 40 mg, 80 mg, or 240 mg.
 11. A method for preparing apharmaceutically acceptable composition, comprising: (1) spraying 5-15weight percent of one or more surface modifying agents ontointragranular components of a granulation, said intragranular componentscomprising: (a) 10-70 weight percent neratinib maleate; (b) 15-65 weightpercent of one or more fillers; (c) 0-8 weight percent of one or moredisintegrants; and (d) 0.2-8 weight percent of one or more glidants; and(2) combining said coated intragranular components with extragranularcomponents of the granulation, said extragranular components comprising:(e) 1-25 weight percent of one or more fillers; (f) 0-8 weight percentof one or more disintegrants; and (g) 0.1-3 weight percent of one ormore lubricants.
 12. The method according to claim 11, wherein thesurface modifying agent is povidone.
 13. A method for treating cancercomprising administering an effective amount of a composition accordingto claim 1; wherein the cancer results from an aberrant tyrosine kinasereceptor.
 14. The composition according to claim 3, wherein the amountof colloidal silicon dioxide, as an intragranular component, is about 2weight percent.
 15. The composition according to claim 3, wherein theamount of neratinib maleate is about 35 weight percent.
 16. Thepharmaceutically acceptable composition of claim 3, comprisingintragranular components: (a) 10-70 weight percent of neratinib maleate;(b) 15-65 weight percent of mannitol and microcrystalline cellulose; (c)0.5-8 weight percent of crospovidone; (d) 0.2-8 weight percent ofcolloidal silicon dioxide; and (e) 5-15 weight percent of povidone; andextragranular components: (f) 1-25 weight percent of microcrystallinecellulose; (g) 1-8 weight percent of crospovidone; and (h) 0.5-3 weightpercent of magnesium stearate.
 17. The pharmaceutically acceptablecomposition of claim 3, comprising intragranular components: (a) 35weight percent of neratinib maleate; (b) about 50 weight percent ofmannitol and microcrystalline cellulose; (c) 3 weight percent ofcrospovidone; (d) 2 weight percent of colloidal silicon dioxide; and (e)5 weight percent of povidone; and extragranular components: (f) 1.5weight percent of microcrystalline cellulose; (g) 2 weight percent ofcrospovidone; and (h) 2 weight percent of magnesium stearate.
 18. Thepharmaceutically acceptable composition of claim 3, comprising 40 mg ofneratinib maleate.